Is LCK p.Arg196Pro (c.587G>C) pathogenic?

LCK p.Arg196Pro (c.587G>C) is classified Uncertain significance in LCK (ClinVar, Multiple submitters, 2 submitters; last evaluated 2025-05-03). AlphaMissense: likely pathogenic (0.9972); Very rare (popmax 8.47e-05%, nfe); Associated with severe combined immunodeficiency due to LCK deficiency.

What condition is associated with LCK p.Arg196Pro (c.587G>C)?

LCK p.Arg196Pro (c.587G>C) is associated with severe combined immunodeficiency due to LCK deficiency (ClinVar).

How common is LCK p.Arg196Pro (c.587G>C) in the general population?

LCK p.Arg196Pro (c.587G>C) is very rare (popmax 8.47e-05%, nfe) (gnomAD).

How is Combined immunodeficiency due to LCK deficiency inherited?

Typically Autosomal recessive (Orphanet). A genetic counselor can assess individual risk for a family.

What do computational predictors say about LCK p.Arg196Pro (c.587G>C)?

AlphaMissense predicts likely pathogenic (score 0.9972) — an in-silico prediction, not a clinical call.

LCK p.Arg196Pro

c.587G>C · rs1640256111 · VCV2194065

Uncertain significance Multiple submitters

Classification

Uncertain significance

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 2 submitters

AlphaMissense

likely pathogenic

0.9972 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 8.47e-05%, nfe)

Missense predictors

3/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

severe combined immunodeficiency due to LCK deficiency

Computational evidence

Protein change
AlphaMissense	0.9972	likely pathogenic
REVEL	0.757	pathogenic-leaning
SaProt	LLR -16.35	damaging
⇒ AlphaMissense, REVEL and SaProt all call this damaging.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 12	GERP 2.2, phastCons 1
Regional constraint	o/e 0.80	unconstrained · MANE · 2,043 bp · p 0.00065 · regional, not allelic
Overall
CADD	27.1	PHRED · no single calibrated threshold — expert panels disagree

ClinVar classifies this uncertain; the computational predictors unanimously lean damaging — a triage signal, not a reclassification

AlphaMissense carries the ACMG weight for missense; REVEL and SaProt are independent agreement signals.

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 8.47e-05% European (non-Finnish) · 1/1,179,974 alleles

Overall 6.84e-05% 1/1,461,870 alleles · very rare

Rarity supports pathogenicity (ACMG PM2); frequency above a disease-specific BA1/BS1 threshold argues against it. A variant frequent in one ancestry group can be near-absent in others, so a single global figure can mislead.

Variant & gene context

Gene: LCK
Protein: p.Arg196Pro
Coding: c.587G>C
MANE Select: NM_005356
dbSNP: rs1640256111
Type: single nucleotide variant
Location: chr1:32276019 (GRCh38)
Gene constraint: LOEUF 0.332 · pLI 1.00 (gnomAD)
Structure: AlphaFold pLDDT 84.12 · 57 PDB
Residue 196: the sh2 domain; the 'interaction with ptprh' region

Full LCK gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Disease context

severe combined immunodeficiency due to LCK deficiency — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

For Combined immunodeficiency due to LCK deficiency (Orphanet):

Inheritance: Autosomal recessive
Onset: Infancy, Neonatal

Similar variants

LCK p.Arg196Gln Uncertain significance ★ ⚠ same residue
LCK p.Arg196fs Likely pathogenic ★ same residue
LCK c.631+3G>A Uncertain significance ★★ same condition
LCK p.Ala284Gly Uncertain significance ★★ ⚠ same condition
LCK p.Arg219Gln Uncertain significance ★★ ⚠ same condition
LCK p.Arg222His Uncertain significance ★★ ⚠ same condition
LCK p.Arg461His Uncertain significance ★★ ⚠ same condition
LCK p.Asn40Ser Uncertain significance ★★ ⚠ same condition

Built on 18 open, versioned datasets — ClinVar, gnomAD, AlphaMissense, REVEL, ClinGen & more — plus Sugi Variant's own cross-source analysis. Source data 2026-01–2026-10, ClinVar 2026-10. Full sources & versions →

Cite Sugi Variant

Gür T. Sugi Variant: A Deterministic Per-Variant Germline Reference from a Knowledge Graph for Humans and AI Agents. 2026. doi:10.5281/zenodo.21509445. This variant: https://sugi.bio/variant/lck-p-arg196pro (accessed [today's date]).

Preprint & method: sugi.bio/variant/method Machine-readable: this page as Markdown